Open AccessRole of Rho kinase and Na + /H + exchange in hypoxia‐induced pulmonary arterial smooth muscle cell proliferation and migration
Author(s) -
Walker Jasmine,
Undem Clark,
Yun Xin,
Lade Julie,
Jiang Haiyang,
Shimoda Larissa A.
Publication year - 2016
Publication title -
physiological reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 39
ISSN - 2051-817X
DOI - 10.14814/phy2.12702
Subject(s) - hypoxia (environmental) , in vivo , ex vivo , intracellular ph , pulmonary hypertension , homeostasis , rho associated protein kinase , hypoxic pulmonary vasoconstriction , endocrinology , medicine , chemistry , biology , kinase , intracellular , biochemistry , oxygen , microbiology and biotechnology , organic chemistry
Abnormal proliferation and migration of pulmonary arterial smooth muscle cells ( PASMC s) are hallmark characteristics of vascular remodeling in pulmonary hypertension induced by chronic hypoxia. In this study, we investigated the role of the Na + /H + exchanger ( NHE ) and alterations in intracellular pH (pH i ) homeostasis in meditating increased proliferation and migration in PASMC s isolated from resistance‐sized pulmonary arteries from chronically hypoxic rats or from normoxic rats that were exposed to hypoxia ex vivo (1% or 4% O 2 , 24–96 h). We found that PASMC s exposed to either in vivo or ex vivo hypoxia exhibited greater proliferative and migratory capacity, elevated pH i , and enhanced NHE activity. The NHE inhibitor, ethyl isopropyl amiloride ( EIPA ), normalized pH i in hypoxic PASMC s and reduced migration by 73% and 45% in cells exposed to in vivo and in vitro hypoxia, respectively. Similarly, EIPA reduced proliferation by 97% and 78% in cells exposed to in vivo and in vitro hypoxia, respectively. We previously demonstrated that NHE isoform 1 ( NHE 1) is the predominant isoform expressed in PASMC s. The development of hypoxia‐induced pulmonary hypertension and alterations in PASMC pH i homeostasis were prevented in mice deficient for NHE 1. We found that short‐term (24 h) ex vivo hypoxic exposure did not alter the expression of NHE 1, so we tested the role of Rho kinase ( ROCK ) as a possible means of increasing NHE activity. In the presence of the ROCK inhibitor, Y‐27632, we found that pH i and NHE activity were normalized and migration and proliferation were reduced in PASMC s exposed to either in vivo (by 68% for migration and 22% for proliferation) or ex vivo (by 43% for migration and 17% for proliferation) hypoxia. From these results, we conclude that during hypoxia, activation of ROCK enhances NHE activity and promotes PASMC migration and proliferation.